The present invention relates to the synthesis of non-steroidal anti-inflammatory drugs (xe2x80x9cNSAIDsxe2x80x9d). More particularly, the invention relates to the synthesis of 2-aryl-3-hydroxy-propenoic acid esters and 2-aryl propenoic acid esters, which are key intermediates in the production of certain NSAIDs and their pharmaceutically acceptable salts.
Efficient practical routes to pharmaceutically-active compounds are in great demand. Manufacturers constantly seek synthetic routes that are environmentally friendly with respect to solvent volume, purity, yield and waste reduction. In addition, the cost of manufacturing drugs generally decreases as the number of steps in the synthetic route decreases. This is particularly true with respect to (S)-2-(6-methoxy-2-naphthyl)propanoic acid, which is also known as naproxen.
Naproxen is one of the most potent NSAIDs currently available, and as a result is extremely popular with consumers, generating sales of over one billion dollars annually.
Unfortunately, naproxen is difficult to synthesize in an efficient and environmentally friendly manner. Since naproxen is the optically active (S) form of 2-(6-methoxy-2-naphthyl)propanoic acid, and is presently marketed in a composition free of the (R) stereoisomer, it has been proposed to produce naproxen using a catalytic asymmetric hydrogenation process.
Specifically, it has been proposed to synthesize naproxen from 2-(6-methoxy-2-naphthyl)propenoic acid in a catalytic asymmetric hydrogenation reaction using a ruthenium (S)-BINAP catalyst or a tol-BINAP-based catalyst. This synthesis route is generally shown in FIG. 1 below. 
While this is an extremely efficient and effective process, it has not been utilized to date on a commercial scale due to the difficulty and high cost involved in producing the 2-(6-methoxy-2-naphthyl)propenoic acid precursor compound. Therefore, an efficient, cost-effective and environmentally-friendly process for making 2-(6-methoxy-2-naphthyl)propenoic acid is needed.
An efficient, cost-effective and environmentally-friendly process for making 2-(6-methoxy-2-naphthyl) propenoic acid ester, which can then easily be converted to 2-(6-methoxy-2 naphthyl) propenoic acid, and then from there to naproxen, using known techniques, has been discovered. Moreover, this process can be used to make other 2-aryl substituted propenoic acid esters, which in turn can be used to produce a wide variety of NSAIDs, including, but not limited to, ibuprofen, ketoprofen, flurbiprofen, fenaprofen, indoprofen, cicloprofen, carprofen, pirprofen, suprofen, and tiaprofenic acid.
For the production of NSAIDs, an aryl aldehyde, where the aryl group is a substituted or unsubstituted aromatic or heteroaromatic group, is reacted with an alkyldiazoacetate in the presence of a catalytic amount of fluoroboric acid or an iron Lewis acid to provide a 2-aryl-3-hydroxy-propenoic acid ester. The 2-aryl-3-hydroxy-propenoic acid ester is then reduced to provide a 2-aryl-propenoic acid ester, which can be converted to the desired NSAID by hydrolysis and hydrogenation.
Preferably, the substituted or unsubstituted aromatic or heteroaromatic group is (a) a phenyl group; (b) a phenyl group substituted with one, two or three substituents independently selected from alkyl halogen, cyano, carboxy, cycloalkyl, nitro, alkoxy, phenyl or substituted phenyl, alkylcarbonyl of one to ten carbon atoms, benzoyl or substituted benzoyl, 1-oxo-isoindolyl, phenoxy or substituted phenoxy, azoline or thienylcarbonyl; (c) a naphthyl group; (d) a naphthyl group substituted with one or more of the substituents from (b) above; (e) a fluorenyl group; (f) a carbazoyl group; (g) a carbazoyl group substituted with one or more of the substituents from (b) above; (h) a thienyl group; (i) a thienyl group substituted with one or more of the substituents from (b) above; (j) a pyrrolyl group; (k) a pyrrolyl group substituted with one or more of the substituents from (b) above; (l) a furyl group; and (m) a furyl group substituted with one or more of the substituents from (b) above.
The present invention relates to the synthesis of compounds of the formula: 
where Ar is a substituted or unsubstituted aromatic or heteroaromatic group. The term xe2x80x9caromaticxe2x80x9d refers to a ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, anthryl, phenanthryl, tetrahydronaphthyl, indanyl, indenyl and the like. Aromatic groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, dialkylamino, aminocarbonyl, aminocarbonylalkoxy, aryl, arylalkyl, arylalkoxy, aryloxy, cyano, nitro, carboxy, cycloalkyl, cycloalkylalkyl, carboxyalkoxy and phenyl.
The term xe2x80x9calkylxe2x80x9d as used herein refer to straight or branched chain containing from one to ten carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term xe2x80x9calkoxyxe2x80x9d as used herein refers to ROxe2x80x94, wherein R is a alkyl group, as defined above.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an aliphatic ring system having three to ten carbon atoms and one to three rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl and like.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to one of the electronegative elements of group VIIA of the periodic table, such as fluorine, chlorine, bromine, iodine and astatine.
The term xe2x80x9cheteroaromaticxe2x80x9d refers to any 5-, 6-, 7-membered aromatic ring containing one or more nitrogen, oxygen, or sulfur atoms, or any combination thereof. The term xe2x80x9cheteroaromaticxe2x80x9d also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or another heterocyclic ring (for example, indolyl, quinolyl, benzofuryl or benzothienyl and the like).
Heteroaromatics include, but are not limited to, pyrrolyl, pyrrolinyl, imidazolyl, pyridyl, indolyl, furyl, thienyl, isoindolyl.
Preferably, the substituted or unsubstituted aromatic or heteroaromatic group is (a) a phenyl group; (b) a phenyl group substituted with one, two or three substituents independently selected from alkyl, halogen, cyano, carboxy, cycloalkyl, nitro, alkoxy, phenyl or substituted phenyl, alkylcarbonyl of one to ten carbon atoms, benzoyl or substituted benzoyl, 1-oxo-isoindolyl, phenoxy or substituted phenoxy, azoline or thienylcarbonyl; (c) a naphthyl group; (d) a naphthyl group substituted with one or more of the substituents from (b) above; (e) a fluorenyl group; (f) a carbazoyl group; (g) a carbazoyl group substituted with one or more of the substiuents from (b) above; (h) a thienyl group; (i) a thienyl group substituted with one or more of the substituents from (b) above; (j) a pyrrolyl group; (k) a pyrrolyl group substituted with one or more of the substituents from (b) above; (l) a furyl group; and (m) a fturyl group substituted with one or more of the substituents from (b) above.
More preferably, the process of the present invention is used to produce NSAID compounds of formula (IV) above such as naproxen (Ar is 6-methoxy-2-naphthalenyl), ibuprofen (Ar isp-isobutylphenyl), ketoprofen (Ar is m-benzoylphenyl), flurbiprofen (Ar is 2-fluoro-4-biphenyl), fenaprofen (Ar is m-phenoxyphenyl), indoprofen (Ar is p-(1-oxo-2-isoindolinyl)-phenyl), cicloprofen (Ar is fluorenyl), carprofen (Ar is 6-chlorocarbazolyl), pirprofen (Ar is 3-chloro-4-(3-pyrrolin-1-yl)-phenyl), tiaprofenic acid (Ar is 5-benzoyl-2-thienyl), and suprofen (Ar is p-2-thienoyl-phenyl).
Most preferably, the process of the present invention is used to manufacture naproxen.
The compounds of formula (IV) are produced by reacting an aldehyde of the formula: 
where Ar is as described above, with an alkyldiazoacetate of the formula N2CHCOOR, where R is an alkyl group in the presence of catalytically effective amount of either a Bronsted acid or a Lewis acid, to produce a 2-aryl-3-hydroxy propenoic acid ester of the formula: 
where Ar and R are as described above.
The term xe2x80x9cBronsted acidxe2x80x9d refers any molecule or ion that can donate a hydrogen ion (H+) to another molecule or ion by forming a bond with two electrons to form a second molecule or ion. Examples of suitable Bronsted acids that can be used include, but are not intended to be limited to, fluoroboric acid, perchloric acid, sulfuric acid, hydrohalic acid, nitric acid, triflic acid and phosphoric acid. The use of fluoroboric acid (HBF4) is preferred. The Bronsted acid, if used, should generally be present in an amount from about 0.01 to about 1 molar equivalent per equivalent of compound (I), and is preferably present in an amount of from about 0.05 to about 0.1 molar equivalents per equivalent of compound (I).
The term xe2x80x9cLewis acidxe2x80x9d refers to any molecule or ion that can combine with another molecule or ion by forming a bond with two electrons to form a second molecule or ion. Examples of suitable Lewis acids that can be used in the present invention include, but are not intended to be limited to, zinc chloride, tin chloride, aluminum chloride, boron trifluoride, and iron Lewis acids, such as [CpFe(CO)2(THF)]+. Use of [CpFe(CO)2(THF)]+ is preferred. If a Lewis acid is used, it should generally be present in an amount from about 0.01 to about 0.5 molar equivalents per equivalent of compound (I) and is preferably present in an amount of from about 0.01 to about 0.1 molar equivalents per equivalent of compound (I). The alkyldiazoacetate is preferably ethyldiazoacetate or methyldiazoacetate and should generally be present in an amount of from about one to about two molar equivalents per equivalent of compound (I).
The reaction is carried out at a temperature of from +40xc2x0 C. to about xe2x88x9290xc2x0 C., preferably at a temperature from about room temperature to about xe2x88x9278xc2x0 C., in a solvent that is suitable for use with the above reactants. Any polar or nonpolar solvent or mixture of polar and nonpolar solvents can be used in the process of the present invention. Suitable solvents include, but are not limited to, pentane, hexane, ether, methylene chloride, cyclohexane, xylene, mesitylene, chlorobenzene, tetrahydrofuran, 1,4-dioxane, fluorobenzene and mixtures thereof. The use of methylene chloride is preferred.
The resulting compound of formula (II) above is then reduced in the presence of an alkyl amine where alkyl is as described above to produce a 2-aryl propenoic acid ester of the formula: 
where Ar and R are as described above.
Suitable reducing agents for use in producing the compound of formula (II) above include, but are not limited to, NH3 in Li, Na, or K; metal hydrides (including, but not limited to, NaH, LiH, BH3, NaBH4, LiAlH4, LiBH4, Zn(BH4)2, NaBH3CN, LiHBEt3, AlH3, and Et3SiH); H2/Pd; H2/Pt; and HCHO in acid or in base. A preferred reducing agent is BH3 complexed with polar protic or aprotic solvents. The most preferred reducing agent is BH3.THF. The reducing agent should be present in an amount from about 0.5 to about 3 molar equivalents per equivalent compound (II), with an amount of from about 1 to about 1.5 molar equivalents per equivalent of compound (II) being preferred. Any polar protic or aprotic solvent can be used in the process of the present invention. Suitable solvents include, but are not limited to, alcohol, ether, tetrahydrofuran (xe2x80x9cTHFxe2x80x9d), 1,4-dioxane, and mixtures thereof. The use of THF is preferred.
The reaction should also proceed in the presence of an alkyl amine or an aryl amine, where alkyl and aryl are as described above. Of the amines, secondary amines are preferred for use in the present invention. The term xe2x80x9csecondary aminexe2x80x9d refers to dialkyl amine, alkylarylamine, diarylamine, or heterocyclic amines, where alkyl and aryl are as described above. The term xe2x80x9cheterocyclicxe2x80x9d as used herein refers to any 3- or 4-membered ring containing nitrogen atom or a 5-, 6-, or 7-membered ring containing one, two or three nitrogen atoms, or one nitrogen and one oxygen atom. Of the secondary amines, the use of pyrrolidine, piperidine or oxazoborolidine is preferred. The secondary amine should be present in an amount from about 0.01 to about 1 molar equivalent per equivalent of compound (II), with an amount of from about 0.05 to about 0.2 molar equivalents being preferred.
The resulting 2-aryl-propenioc acid ester compound of formula (III) can then be hydrolyzed to its corresponding 2-aryl-propenoic acid by known techniques using KOH, NaOH or Ba(OH)2. That compound can then be converted to its corresponding 2-aryl-propanoic acid (an NSAID) of formula (IV) by known hydrogenation reactions, such H2/Pd or H2/Ni. The hydrolysis and hydrogenation steps may also be reversed, if desired. The 2-aryl-propenoic acid of formula (IV) can also be converted to one of its pharmaceutically acceptable salts by known techniques, if desired. In this manner, NSAIDs such as naproxen, ibuprofen, ketoprofen, flurbiprofen, indoprofen, carprofen, suprofen, fenaprofen, and their pharmaceutically acceptable salts can be made.
While the above process can be used to make a wide variety of NSAIDs, it is preferably used in the production of naproxen and its pharmaceutically acceptable salts, especially the sodium salt. To make naproxen, which has the formula: 
6-methoxynaphthyl aldehyde of the formula: 
is used as the starting material, and is reacted with an alkyldiazoacetate (N2CHCOOR) where R is alkyl as described above, to yield 2-(6-methoxy-2-naphthyl)-3-hydroxy propenoic acid ester, which has the formula: 
where R is as described above.
That compound is then preferably reduced with BH3.THF in the presence of a secondary amine, preferably piperidine, pyrrolidine or oxazoborolidine, to yield 2-(6-methoxy-2-naphthyl)propenoic acid ester, which has the formula: 
where R is as described above.
The compound of formula (VII) can be converted to 2-(6-methoxy-2-naphthyl) propanoic acid, naproxen, by first hydrolyzing it to form 2-(6-methoxy-2-naphthyl) propenoic acid of the formula: 
That compound is then reduced to naproxen by known catalytic asymmetric hydrogenation processes, using, for example a Ru-BINAP catalyst disclosed in U.S. Pat. No. 5,198,561, or a tol-BINAP catalyst disclosed in Ohta et al., J Org-Chem., 1987, 52, 3174. The resulting naproxen can be converted to one of its pharmaceutically acceptable salts by known techniques, if desired.